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Partial Adrenal Suppression with Prolonged Use of Depo-Provera

Nur Aisyah Zainordin, Fatimah Zaherah Mohd Shah and Rohana Abdul Ghani

Endocrine Unit, Department of Internal Medicine, Faculty of Medicine, Universiti Teknologi MARA, Selangor, Malaysia

Received ABSTRACT 5th April 2019 Received in revised form A 49-year old patient presented with symptoms of adrenal suppression following an attempt to 23rd May 2019 withdraw Depo-Provera or Depot Medroxyprogesterone Acetate (DMPA) injection. She had Accepted been receiving DMPA injections for the past 16 years for contraception. She was initially th 12 June 2019 prescribed DMPA by her gynaecologist but later on began obtaining the medication directly from a private pharmacy without prior consultation from her gynaecologist. Clinically, she had Corresponding author: been experiencing significant weight gain and appeared cushingoid. Blood investigations Nur Aisyah Zainordin confirmed partial adrenal suppression with presence of an adrenal incidentaloma. This case Endocrine Unit, reports a known side effect of DMPA but occurring at a much lower dose than previously Department of Internal Medicine, described. It also highlights the need to increase the awareness of the insidious side effect of DMPA and to avoid unsupervised use of the drug. Faculty of Medicine,

University Technology MARA, KEYWORDS: Addison, Adrenal Suppression, Depro-Provera, Depot Jalan Hospital, 47000, Medroxyprogesterone Acetate (DMPA), cortisol Sungai Buloh, Selangor. Tel: +60192597751 Email: [email protected]

INTRODUCTION She is a working mother of 5, who was started on DMPA treatment following the birth of her last child 16 Depo-Provera (DMPA) is one of the progestin -only years ago. She has not been attending any regular methods used for contraception. It was originally follow-ups with her gynaecologist and obtained the 150 approved to treat endometriosis and certain cancers but mg three-monthly injections of DMPA from a nearby is most commonly also used as a contraceptive [1]. A pharmacy. She has noted progressive weight gain of 90-day dosage of 150 mg of DMPA has been associated approximately 30kg within the past 10 years, which she with side effects, including irregular menstruation, attributed to poor dietary habits and sedentary lifestyle. anxiety, headaches, weakness, abdominal pain, weight She became amenorrheic after a year of treatment with gain and amenorrhoea [2]. However, the effect of occasional spotting. DMPA in suppressing the at a dose of Five years ago, at the age of 44, she stopped 150mg has never been reported before. We report a taking the DMPA injection, following advice from her case of a woman who had been on DMPA for 16 years GP. However, a few weeks after stopping the DMPA and who developed symptoms of adrenal suppression. she became severely lethargic, and suffered headaches CASE PRESENTATION and erratic mood swings, which subsequently led to her A 49-year old lady was referred by her General low mood. She attributed her condition to the cessation Practitioner for severe lethargy and generalized body of the DMPA and recommenced the injections, which pain during her attempt to stop her DMPA treatment. immediately alleviated her symptoms and boosted her energy levels.

Vol 4(1) (2019) 64-66 | jchs-medicine.uitm.edu.my | eISSN 0127-984X 64

Partial Adrenal Suppression with Depo-Provera

any symptoms of hypo-cortisolism. Six months later, She has no other medical condition and denies taking her short synacthen test was normal. She however does any supplement or traditional medications. have occasional emotional lability and remains During her current presentation, she was still on amenorheic. DMPA injection to help her with her mood swings and energy levels. She was however still complaining of DISCUSSION occasional lethargy, headache, generalized body pains The contraceptive effect of three monthly DMPA and mood swings but had expressed her wish to injections are due to its anti-oestrogenic, anti- discontinue with her DMPA. On clinical examination, androgenic and anti-gonadotrophic actions, which she appeared plethoric with apparent moonlike-facies. prevent follicular maturation and ovulation and causes There was acanthosis nigricans but no paper-thin , thickening of cervical mucus that inhibits sperm entry no striae, no bruising and no hirsutism. There was into the uterus [3]. evidence of proximal myopathy, which was confined to DMPA has been identified to have a notable the lower limbs. Her weight was 110kg with a BMI of cortisol-like activity on the hypothalmic- 47 kg/m2. Her blood pressure was 128/78 (sitting) and pituitary-adrenal (HPA) axis since the 1970s when 120/70 (standing) with a rate of 79 beats per patients on DMPA presented with cushingoid minute. Chest and cardiovascular examination were symptoms, such as weight gain, facial swelling and unremarkable. Her abdomen was soft with no generalised edema [4].This cortisol-like effect is organomegaly. believed to exert a action on the Laboratory investigations showed reduction in or the pituitary leading to low plasma early morning cortisol level at 7am; 140 nmol/L ACTH, suppression of adrenal function and decreased (N=170-536 nmol/L). Serum level was cortisol secretion. Mild suppression of the hypothalmic- normal; 106.8 pmol/L (normal level: <18.4-183 pituitary-adrenal axis has been reported in 10 children pmol/L) as well as , which was 0.9 nmol/L who received 100-150mg per week of DMPA for the (normal level: 0.3-2.5 nmol/L). However, her follicular treatment of precocious puberty [4]. A study done by stimulating level was low at 8.76 IU/L (normal Hellman et al [5] showed a 76% reduction in plasma level: 26-135 IU/L). Similarly, her cortisol concentration in 12 breast cancer patients who was also low at 2.92 IU/L (normal level: 7.7-59 IU/L). were given weekly doses of 400, 700 or 1200 mg of Renal profile and function test otherwise were DMPA for 6-24 months. Another study also showed normal. partial adrenal suppression in postmenopausal women CT scan of the adrenal showed evidence of left with disseminated breast cancer who received high adrenal incidentaloma - 0.9 x 0.9cm. HU (plain): 5-40 doses of DMPA of up to 250 mg four times daily[6]. (average 23), HU (portovenous): 100-150 (average Patients who developed adrenal suppression following 125), HU (delayed): 35-55 (average 45) with absolute DMPA treatment were reported to be older and perhaps washout of 78% and relative washout 64%. could be more sensitive to the anabolic effects of DMPA was stopped for the second time and a DMPA than other patients [7]. Malik et al [8] reported short synacthen test was performed 3 months later and a case-study of eleven patients who had received the results showed partial response of cortisol to DMPA following treatment for breast carcinoma and synacthen = 0 hour: 156 nmol/L (normal value in hypernephroma. The duration of DMPA therapy ranged morning 170-536 nmol/L), at 30 mins 384.9 nmol/L and from 6 to 90 months. Four of the eleven patients had at 60 min 429.7 nmol/L (N=increment >200nmol/L low basal cortisol levels and subnormal responses to above baseline and peak >550 nmol/L. At this juncture, synacthen and two patients had a borderline response. she was still complaining of lethargy and low mood. Eight patients had ACTH levels at or below the She was treated with low dose 5 detection limit of the assay. mg bd for 1 year before it was stopped. At subsequent clinic follow up sessions, she appeared well, and denied

65 Vol 4(1) (2019) 64-66 | jchs-medicine.uitm.edu.my | eISSN 0127-984X

Partial Adrenal Suppression with Depo-Provera

To our knowledge, there have been no reports REFERENCES to date, on partial or complete adrenal suppression due to prolonged use of DMPA, particularly at a dose of 150 1. Morrison, Charles S., Hormonal contraception mg when used as a contraceptive. Our patient presented and HIV: an unanswered question. The Lancet with typical symptoms of hypo-cortisolism during the Infect Dis. 2011;12(1):2-3 period of cessation of DMPA therapy. This was 2. Spevack E. The Long-term Health Implications confirmed by the presence of partial adrenal of Depo-Provera. Integ Med. 2013; (12) No. 1 suppression following the synacthen test. Her CT scan, 3. FDA highlights of prescribing information. which showed adrenal incidentaloma, highlights the http://www.accessdata.fda.gov/drugsatfda_doc likelihood that her condition was due to the DMPA s/label/2010/020246s036lbl.pdf. 2017. therapy. This case highlights 2 major points, which Accessed 5 Jun 2018. differ from previous reports. The first being the 4. Matthews JH, Abrams CAL, Morishima A. prolonged and unsupervised use of the injectable drug Pituitary-adrenal function in ten patients and the second being that even at relatively low doses receiving medroxyprogesterone acetate for true long-term usage of DMPA can lead to hypo-cortisolism. precocious puberty. Clin Endocrinol Metab 1970; 30: 653-8 CONCLUSION 5. Hellman L, Yoshida K, Zumoff B et al. The Depo-Provera or DMPA has been associated with Effect of Medroxyprogesterone Acetate on the adrenal suppression due to cortisol-like glucocorticoid Pituitary-Adrenal Axis. Clin Endocrinol and activity, which provides negative feedback effects on Metab. 1976; 42 (5): 912-917. the hypothalamus or pituitary. This results in low 6. van Veelen H, Willemse PH, Sleijfer DT et al. plasma ACTH levels and consequently also decreased Mechanism of adrenal suppression by high- plasma cortisol. Our patient developed partial adrenal dose medroxyprogesterone acetate in breast suppression due to prolonged, unsupervised cancer patients. Cancer Chemother prescription and use of a low dose DMPA. Thus, Pharmacol. 1985;15(2):167-70 clinicians should be wary of this insidious side effect of 7. V. Hug, S. Kau, G.N. Hortobagyi & L. Jones. a very common drug even when used at low doses. Adrenal failure in patients with breast carcinoma after long-term treatment of cyclic Conflict of Interest alternating oestrogen progesterone Br J Cancer (1991), 63, 454-456 Authors declare none. 8. K J Malik, K Wakelin, S Dean et al. Cushing's syndrome and hypothalamic-pituitary adrenal Acknowledgements axis suppression induced by We would like to thank all clinicians and the patient that medroxyprogesterone acetate. Ann cu Biochem provided clinical information. 1996; 33: 187-189

66 Vol 4(1) (2019) 64-66 | jchs-medicine.uitm.edu.my | eISSN 0127-984X